Antigenic diversity provides the malaria parasite the means to evade the host immune system, and represents an obstacle to developing a safe and effective malaria vaccine. If the protection conferred by a vaccine is allele-specific, immunization may select allelic variants of these genes in the parasite population. Such changes in the parasite population structure could greatly affect the efficacy of a vaccine. In most vaccine trials to date, the end point for the immunogenicity studies has been antibody measurements. It is generally assumed that antibodies mediate the important immune responses to bloodstage antigens including AMA-1, but the nature of the protective immune response elicited by this and other vaccine candidates, if any, is not known. A cellular immune response, whether in the blood or liver stages of the parasite, may be important for protection against malaria disease and infection, and antibody responses detected in standard assays may not be those most important for protection. Finally, standard immunogenicity measurements do not provide information about the duration of the vaccine-induced immune response or about the ability of a vaccine to elicit immunity that protects against parasites that are genetically different from the strain of vaccine origin. This project will assess the role of allelic diversity in vaccine efficacy and immune responses, and measure the duration and degree of heterologous protection provided by the AMA-1 vaccine candidate FMP2.1/AS02A. This will be accomplished though genetic and immunological analyses of existing samples and those obtained from a cross-sectional survey and from the trials described in Project 1. In addition, molecular studies will provide a direct measure of strain-specific vaccine efficacy in the Phase 2B trial.